Description
Cervical cancer is a malignant neoplasm arising from the cells of the cervix. It is predominantly caused by persistent high-risk human papillomavirus (HPV) infection. It’s classified mainly into two types: squamous cell carcinoma, which makes up approximately 70% of cases, and adenocarcinoma.
Pathogenesis
Cervical cancer pathogenesis typically begins with an infection by high-risk types of HPV (16 and 18), which integrate their DNA into the host cell genome, disrupting normal cell function and leading to dysregulation of cell growth and division. Over time, these changes can accumulate, potentially developing into pre-cancerous changes (cervical intraepithelial neoplasia, or CIN) and eventually invasive cancer.
Epidemiology, Risk Factors & Associations
Cervical cancer is the fourth most common cancer in women worldwide and third mod common gynaecological malignancy. Risk factors include:
- HPV infection: Virtually all cervical cancers are associated with high-risk HPV types (particularly types 16 and 18).
- HPV vaccination: There’s a strong negative association with HPV vaccination and the development of cervical cancer, as the vaccine protects against HPV types 16 and 18 which are responsible for the majority of cervical cancers globally.
- Immunosuppression: Women with weakened immune systems (such as those with HIV/AIDS) have a higher risk of developing cervical cancer.
- Smoking: Tobacco use doubles the risk of cervical cancer.
- Oral contraceptives: Long-term use (5 years or more) can increase the risk of cervical cancer in women with HPV.
- Multiple full-term pregnancies: Women who have had three or more full-term pregnancies have an increased risk.
- Young age at first full-term pregnancy: Women who were younger than 17 years when they had their first full-term pregnancy are almost twice as likely to get cervical cancer later in life than women who waited to get pregnant until they were 25 years or older.
- Family history: Women with a sister or mother who had cervical cancer have two to three times the risk of developing the disease.
- Low socioeconomic status: Women from low-income backgrounds are at a higher risk due to decreased access to screening and early detection services.
- Co-infection with Chlamydia trachomatis: Some studies have seen an increased risk of cervical cancer with this sexually transmitted infection.
- Diet: Diets low in fruits and vegetables are associated with an increased risk.
Screening programs
Successful cervical screening programs (Pap tests and HPV DNA testing) are associated with lower rates of cervical cancer.
Clinical Features
- Early Stages: May be asymptomatic or present with abnormal vaginal bleeding (intermenstrual bleeding, postcoital bleeding, or postmenopausal bleeding).
- Advanced Stages: Pelvic pain, back pain, urinary symptoms (due to urinary tract obstruction), lower extremity oedema and/or deep venous thrombosis due to pelvic lymph node involvement, weight loss, fatigue, and anaemia.
Complications
- Local Spread: Invasion of the bladder or rectum causing symptoms like haematuria or haematochezia.
- Distant Metastasis: Spread to lungs, liver, or bones resulting in symptoms related to these organs.
- Obstructive Uropathy: Leading to renal failure.
- Fistula Formation: Between the bladder and vagina (vesicovaginal fistula) or between the rectum and vagina (rectovaginal fistula), causing leakage of urine or faeces into the vagina.
Subtypes
- Squamous Cell Carcinoma: Comprises 70% of cervical cancers and is linked to HPV types 16 and 18.
- Adenocarcinoma: Comprises about 25% of cases and is often associated with HPV as well.
- Adenosquamous Carcinoma: Rare subtype containing components of both squamous cell carcinoma and adenocarcinoma.
- Adenoma Malignum: Rare subtype of cervical adenocarcinoma characterised by minimal deviation from normal glandular cells. Possibly associated with Peutz-Jeghers syndrome and mucinous ovarian neoplasms.
- Small Cell Carcinoma, Neuroendocrine Tumours, and Others: Very rare subtypes.
Pathological Features
Histopathology
- Squamous Cell Carcinoma: Malignant squamous cells with variable degrees of differentiation. Presence of keratin pearls and intercellular bridges in well-differentiated tumours.
- Adenocarcinoma: Malignant glandular cells forming variable architectures including papillary, mucinous, and endometrioid patterns.
- Adenoma Malignum: Characterised by the presence of well-differentiated glandular cells that closely resemble the benign glandular cells of normal cervical tissue.
Immunohistochemistry
- Squamous Cell Carcinoma: Positive for p63 and CK5/6, negative for CEA and vimentin.
- Adenocarcinoma: Positive for CEA, negative for p63 and CK5/6.
Molecular Pathology
- PCR and nucleic acid hybridisation: Presence of high-risk HPV DNA, particularly HPV 16 and 18 from cervical swabs (Pap smear or cervical biopsy)
Radiological Features
General Features
- Adenoma Malignum: Classic appearance is of a multicystic mass with solid components extending from the endocervical glands to the deep cervical stroma.
MRI
- T1-weighted Images: Cervical tumours typically appear isointense or hypointense to the normal cervical stroma. Adenocarcinomas may show high signal intensity areas due to mucin production.
- T2-weighted Images: Tumours are generally hyperintense relative to the normal cervical stroma. The tumour can often be seen distorting the normal architecture of the cervix.
- Post-contrast T1-weighted Images: Tumours typically enhance less than the normal cervical stroma. The pattern of enhancement can provide clues about the degree of tumour vascularity and necrosis.
- Diffusion-weighted Imaging (DWI): Tumours usually restrict diffusion and therefore appear bright on high b-value images and dark on the corresponding ADC map.
CT
- Pre-contrast: Cervical tumours are typically isodense to the normal cervix.
- Post-contrast: Enhancement pattern similar to that on MRI, with tumours typically enhancing less than the normal cervical stroma.
- Assessment of Lymph Nodes: CT can also evaluate the presence of pelvic and para-aortic lymphadenopathy, a sign of metastatic disease.
- Assessment of Distant Metastases: CT of the chest, abdomen, and pelvis can evaluate for distant metastases, particularly to the lungs, liver, and bones.
PET-CT
- FDG-PET: Cervical carcinomas typically show increased FDG uptake, which can help distinguish tumour from normal tissue and identify areas of metastatic disease. FDG uptake may be increased in the primary tumour, involved lymph nodes, and any areas of distant metastases.
- CT Component: The CT component of the study provides anatomic detail to correlate with the metabolic information from the PET images. This can help localise areas of abnormal FDG uptake to specific anatomic structures.
Ultrasound
- Transabdominal or Transvaginal: Tumours usually appear as hypoechoic masses in the cervix. However, ultrasound is not the first-choice modality for cervical cancer due to limited field of view and operator dependence.
- Doppler: Increased vascularity may be noted in the tumour.
- Assessment of Lymph Nodes: Ultrasound can also assess for the presence of pelvic lymphadenopathy.
Grading and Staging
Staging is based on the FIGO system which ranges from Stage IA (minimal invasion) to Stage IVB (distant metastasis). It’s a clinically based system but increasingly utilises radiological and pathological input.
- Stage 0: Carcinoma in situ (pre-invasive stage) where abnormal cells are present only on the surface layer of the cervix.
- Stage I: Cancer is confined to the cervix.
- Stage IA: Microscopic invasion with no visible tumour.
- Stage IA1: Invasion less than or equal to 3 mm in depth and less than or equal to 7 mm in width.
- Stage IA2: Invasion greater than 3 mm but less than or equal to 5 mm in depth and less than or equal to 7 mm in width.
- Stage IB: Visible tumour confined to the cervix or microscopic invasion greater than stage IA.
- Stage IB1: Visible lesion measuring greater than 4 cm in greatest dimension.
- Stage IB2: Visible lesion measuring greater than 4 cm in greatest dimension.
- Stage II: Cancer extends beyond the cervix but has not reached the pelvic sidewall or the lower third of the vagina.
- Stage IIA: Involvement of the upper two-thirds of the vagina without parametrial invasion.
- Stage IIB: Parametrial invasion.
- Stage III: Cancer extends to the lower third of the vagina or pelvic sidewall or causes hydronephrosis or non-functioning kidney.
- Stage IVA: Cancer has spread to adjacent organs such as the bladder or rectum.
- Stage IVB: Distant metastasis is present.
Differential Diagnosis
Key differential diagnoses include benign cervical lesions such as nabothian cysts and cervical polyps, other malignancies such as endometrial or ovarian cancer, and other causes of vaginal bleeding or discharge.
Management
Management primarily involves the referral to a specialist gynaecological oncology team. Depending on stage, treatment options range from surgery (e.g., hysterectomy) to chemo-radiotherapy. Vaccination against HPV and cervical screening are crucial for prevention.
If the tumour is limited to a small or focal parametrial involvement, it may still be possible to perform a radical hysterectomy with removal of the adjacent lymph nodes. This procedure aims to remove the cervix, uterus, upper vagina, and the surrounding parametrial tissue. The extent of parametrial resection may be adjusted based on the specific involvement observed.
However, when there is extensive parametrial involvement or infiltration into adjacent structures, a radical hysterectomy alone may not be feasible. In such cases, a more extensive surgical procedure known as exenteration may be considered. Exenteration involves the removal of the cervix, uterus, upper vagina, parametrium, and sometimes adjacent organs such as the bladder or rectum, depending on the extent of the tumor spread. This procedure is more aggressive and associated with increased surgical risks and potential long-term complications.